Multiple myeloma is a neoplastic disease in plasma cells which produce and secrete immunoglobulins (Ig's). The Ig's thus produced are homogeneous proteins called M proteins. The M proteins are observed in the blood in most cases. Known examples of these M proteins include IgG, IgA, BJP, IgD, IgE and IgM. BJP is a protein comprising the L chain of Ig (Bence Jones Protein: BJP) alone. The main focus of this disease resides in bone marrow. Myeloma cells tubercularly proliferate in the bone marrow and thus bone lesions frequently arise. In addition, clinical pictures such as anemia, renal failure and immunodeficiency are observed.
Among all, osteolytic bone lesions are pathognomonic symptoms which are observed in most patients with multiple myeloma. It has been clarified that these bone lesions also affect the prognosis of patients with multiple myeloma and relate to the survival time. Further, bone pain due to bone lesions and pathologic fracture and neuropathy due to spinal compression fracture are causative factors worsening patients' quality of life (QOL). It is known that these bone lesions pathologically include clinical pictures of osteolysis, osteoporosis, bone fracture and combinations thereof. Studies are now under way on the onset mechanism of bone lesions in patients with multiple myeloma. At the present time, it is proposed that parathyroid hormone-related protein (PTHrP), which is a cytokine secreted from myeloma cells and has effects of promoting the formation of osetoclasts and enhancing the activity thereof, might participate therein (Byori to Rinsho, 17(1), 12–17, 1999).
In treating multiple myeloma, use is mainly made of chemotherapies (MP therapy, VAD therapy, C-VAD therapy, polypharmacy, etc.) and chemotherapy with the use of IFN-α. Also, topical radiotherapy and the like are selected depending on the bone lesion conditions (Clinical Oncology, edited by Japan Clinical Oncology Group, published in 1996 by Gan to Kagakuryoho Sha). As the results of the long-term observation on patients with multiple myeloma under chemotherapy, it is reported that a bone resorption marker in urine did not correlate to changes in M proteins due to chemotherapy in many cases, though a tendency toward a decrease in the bone resorption marker was observed in a chemotherapy reaction group showing a decrease of 25% or more in M proteins (Blood, 90, 3743–3750, 1997). Therefore, it becomes more and more necessary to establish a novel therapy for bone lesions accompanying multiple myeloma from the viewpoint of patients' QOL.
As medicines for inhibiting the progress of bone lesions (osteolysis and pathologic fracture) in multiple myeloma, bisphosphonate compounds (hereinafter referred to simply as BP) such as etidronate (7.5 mg/kg body weight, injection), clodronate (800 to 2,400 mg/day, oral, 300 mg/day, injection) and pamidronate (90 mg/4 weeks, intravenous drip) have been marketed in Europe and America. Although it is reported that risedronate (30 mg/day, oral), which is one of BPs, suppressed bone resorption and elevated bone mineral density in patients with multiple myeloma (Bone, Vol. 15, No.1, p. 41–49, 1994), it has not yet approved as a medicine for treating multiple myeloma so far.
In case of using BPs as remedies for bone lesions in multiple myeloma, these compounds are administered in a higher dose than in case of using as remedies for osteoporosis. In addition, BPs are poor in oral absorbability, which considerably elevates the dose of oral BP preparations. The administration of BP in a high dose sometimes worsens the side effects typified by gastrointestinal disorders such as retching, diarrhea and abdominal pain, allergic reaction, hypocalcemia, mental disorders such as insomnia, etc. Therefore, BP preparations are administered to patients parenterally in many cases in practice as parenteral preparations such as injections or intravenous drips. Even clodronate, which is only one BP marketed as oral preparations, should be administered in a very high dose (800 to 2,400 mg/day) and thus burdens a large load to patients. However, BP should be continuously administered to sustain its effects. Therefore, it has been urgently required from the viewpoint of patients' QOL to develop a low-dose oral medicine showing little side effects.
Recently, studies have been made on the anticancer effects of BP's and it is reported that several BP's have an effect of inhibiting cell proliferation in vitro (Britishi J. Haematology, 98, 665–672, 1997), though any clinical usefulness has been proved in none of these cases and some reports rather denying the anticancer effect of BPs are also presented. That is to say, it is reported that pamidronate has been used in a murine model of myeloma, and although no effect on tumor growth was demonstrated, there was evidence of a cytotoxic effect within the bone marrow. It is also reported that risedronate has been used in a murine model of myeloma; however, although there was a clear reduction in bone destruction, no effect on tumor burden was noted (Leukemia and Lymphoma, 32,129–138, 1998). In a patient who was intravenously administered in a higher dose than in prior clinical studies, a transient decrease in a cancer marker was observed. However, it is reported that it is possible that for a cytostatic or even cytotoxic effect to occur, higher dose or more frequent administration of pamidronate is required compared to dosing for its beneficial bone effects (Britishi J. Haematology, 103, 530–532, 1998). Accordingly, it has never been reported hitherto that BPs exert an anticancer effect (i.e., a therapeutic effect on multiple myeloma) in patients with multiple myeloma.
As discussed above, it has been considered that BPs have a therapeutic effect on bone lesions in multiple myeloma but no therapeutic effect on multiple myeloma per se.
On the other hand, it is stated in JP-B-6–99457 and EP 354806 that 1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethane-1,1-bisphosphonic acid (hereinafter referred to as the compound A) or its salt, which is a bisphosphonic acid compound having a fused heterocycle skeleton, suppresses bone resorption, for example, accelerated bone resorption accompanying Bechet'S disease, hypercalcemia, cancer metastasis into bone, osteoporosis, inflammatory joint diseases such as rheumatoid arthritis, etc. (The term “JP-B” as used herein means an “examined Japanese patent publication”.) It is actually confirmed that the compound A exerts a favorable effect of inhibiting bone resorption in osteoporosis. However, no report has been presented so far concerning the therapeutic effect on multiple myeloma and the therapeutic effect on bone lesions in multiple myeloma.